title: Fine-tuning of microRNA-mediated repression of mRNA by splicing-regulated and highly repressive microRNA recognition element.
abstract: BACKGROUND
  MicroRNAs are very small non-coding RNAs that interact with microRNA recognition elements (MREs) on their target messenger RNAs. Varying the concentration of a given microRNA may influence the expression of many target proteins. Yet, the expression of a specific target protein can be fine-tuned by alternative cleavage and polyadenylation to the corresponding mRNA.
  
  
  RESULTS
  This study showed that alternative splicing of mRNA is a fine-tuning mechanism in the cellular regulatory network. The splicing-regulated MREs are often highly repressive MREs. This phenomenon was observed not only in the hsa-miR-148a-regulated DNMT3B gene, but also in many target genes regulated by hsa-miR-124, hsa-miR-1, and hsa-miR-181a. When a gene contains multiple MREs in transcripts, such as the VEGF gene, the splicing-regulated MREs are again the highly repressive MREs. Approximately one-third of the analysable human MREs in MiRTarBase and TarBase can potentially perform the splicing-regulated fine-tuning. Interestingly, the high (+30%) repression ratios observed in most of these splicing-regulated MREs indicate associations with functions. For example, the MRE-free transcripts of many oncogenes, such as N-RAS and others may escape microRNA-mediated suppression in cancer tissues.
  
  
  CONCLUSIONS
  This fine-tuning mechanism revealed associations with highly repressive MRE. Since high-repression MREs are involved in many important biological phenomena, the described association implies that splicing-regulated MREs are functional. A possible application of this observed association is in distinguishing functionally relevant MREs from predicted MREs.
authors.affiliation: Institute of Biomedical Informatics, National Yang-Ming University, Taipei 11221, Taiwan, ROC.
authors.forename: Cheng-Tao
authors.initials: CT
authors.lastname: Wu
authors.forename: Chien-Ying
authors.initials: CY
authors.lastname: Chiou
authors.forename: Ho-Chen
authors.initials: HC
authors.lastname: Chiu
authors.forename: Ueng-Cheng
authors.initials: UC
authors.lastname: Yang
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D017398:Alternative Splicing / Q000235:genetics*; D001483:Base Sequence; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D040901:Proteomics; D059368:RNA Isoforms / Q000235:genetics; D000097584:DNA Methyltransferase 3B
chemical_list: D020413:3' Untranslated Regions; D004248:DNA (Cytosine-5-)-Methyltransferases; D035683:MicroRNAs; D059368:RNA Isoforms; D000097584:DNA Methyltransferase 3B